Uvaol Prevents Group B Streptococcus-Induced Trophoblast Cells Inflammation and Possible Endothelial Dysfunction

Abstract

Group B Streptococcus (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 106 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1β and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.

Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta

“…Therefore, the Raman spectroscopy analysis performed in our study revealed molecular modifications compatible with an increased differentiation towards a more mesenchymal and migratory phenotype of the HTR‐8/SVneo cells expressing the N‐terminal deleted KLF6 protein. Nowadays, few Raman spectroscopy studies performed on trophoblast cells or tissue from human placentas have been reported [75–77], so this work provides additional evidence on the usefulness of this approach to analyze biological samples derived from human placenta.…”

Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis

“…Several studies have indicated that human cell types express a wide range of inflammatory chemokines, cytokines, and antimicrobial proteins, as well as release extracellular traps and undergo cell death in response to GBS exposure ( Table 1 ) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Patras et al infected human epithelial cell types with different strains of GBS, including serotypes I, III, and V, and found that, depending on the strain, the bacteria displayed different abilities to adhere to and survive intracellularly [ 28 ].…”

“…These differences may in part be explained by strain-specific changes in cellular signaling cascades, impacting downstream responses including phagocytosis/survival of GBS, cell death, and cytokine production [ 34 ]. However, specific inflammatory cytokines were universally induced in response to infection in cell types such as placental macrophages, trophoblasts, and endothelial and epithelial cells [ 30 , 31 , 32 , 33 ]. Strong and early IL-1β increase, as well as TNF-α and/or IL-6 increases, were documented following the exposure of ex vivo human choriodecidual tissues or cell lines to live or inactivated GBS [ 33 , 35 ].…”

“…However, specific inflammatory cytokines were universally induced in response to infection in cell types such as placental macrophages, trophoblasts, and endothelial and epithelial cells [ 30 , 31 , 32 , 33 ]. Strong and early IL-1β increase, as well as TNF-α and/or IL-6 increases, were documented following the exposure of ex vivo human choriodecidual tissues or cell lines to live or inactivated GBS [ 33 , 35 ]. Interestingly, uvaol, a component of olive oil, acting as a down regulator of NF-kB translocation, as well as IL-1Ra, dampened the GBS-induced human placental inflammation [ 31 , 33 , 36 ].…”

“…Hence, it is important to conduct studies investigating the role of each pathogen commonly affecting pregnant mothers to specify their immune responses and the resulting neurobehavioral impairments. GBS is a common infection during human pregnancy, which only recently started to be studied preclinically with regard to the profile of GBS-induced MIA and its neurobehavioral impact on the offspring [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”